Tuberculosis following PD-1 blockade for cancer immunotherapy
Tuberculosis following PD-1 blockade for cancer immunotherapy
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DOI：
10.1126/scitranslmed.aat2702
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发表时间：
2019-01-16
影响因子：
17.1
通讯作者：
Sharon, Elad
中科院分区：
文献类型：
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作者：
Barber, Daniel L.;Sakai, Shunsuke;Sharon, Elad
由于通过阻断T细胞抑制性受体PD-1来增强抗肿瘤应答的公认治疗益处，已经提出PD-1阻断也可以用于感染性疾病环境，包括结核分枝杆菌（Mtb）感染。然而，在临床前模型中，Mtb感染的PD-1（-/-）小鼠产生了过度的T（H）1反应，从而导致致命的免疫病理学。在癌症患者中观察到PD-1阻断期间的多例结核病病例，但在人类中，对检查点阻断相关结核病期间的Mtb特异性免疫反应知之甚少。在此，我们再报告两个案例。我们描述了一个病人谁死于播散性结核病后PD-1封锁治疗鼻咽癌，我们检查结核特异性免疫反应的默克尔细胞癌患者谁开发检查点封锁相关的结核病，并成功地治疗感染。抗PD-1给药后，产生干扰素-γ的Mtb特异性CD 4 T细胞在血液中变得更加普遍，几个月后出现结核瘤。在肉芽肿出现之前，Mtb特异性T（H）17细胞、CD 8 T细胞、调节性T细胞和抗体丰度没有变化。这些结果与鼠模型数据一致，表明PD-1阻断增强T（H）1功能可能会增加人类结核病的风险或严重程度。
Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models, Mtb-infected PD-1(-/-) mice mount exaggerated T(H)1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-gamma- producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific T(H)17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting T(H)1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.